Liver fibrosis is the excessive accumulation of extracellular matrix proteins in response to chronic liver injuries, irrespective of the underlying etiology. Although hundreds of millions of people worldwide are at risk of liver fibrosis due to viral infections, alcohol abuse, and obesity, no effective drug is currently available for treating this disease. Advanced liver fibrosis leads to cirrhosis and potentially to liver failure, for which the only effective treatment is liver transplantation. The total public health burden of this disease is incalculable, and efficacious therapies are urgently needed. A recent study has shown that activated hepatic stellate cells, which are the major source of extracellular matrix in CCl4-induced liver injury, undergo cellular senescence. The senescent stellate cells express anti-fibrotic genes and are targeted for removal by natural killer cells, thereby limiting fibrosis and facilitating resolution of the healing response. This finding uncovers a programmed mechanism that invokes cellular senescence to control liver fibrosis, although the molecular signals that trigger senescence are unknown. Our recent studies have identified the matricellular protein CCN1 as a compelling candidate for the regulator of this mechanism. CCN1 can drive fibroblasts into senescence through interaction with its receptors, integrin 61 and heparan sulfate proteoglycans, and activate the expression of anti-fibrotic genes characteristic of senescent cells. Knock-in mice expressing a senescence-defective Ccn1 allele suffer exacerbated fibrosis upon CCl4-induced liver injury, concomitant with loss of senescent cells. We hypothesize that CCN1 is the key regulator of cellular senescence and acts to limit fibrosis in chronic liver injuries, and we will scrutinize its functions in four specific aims: (1) to conduct a genetic analysis of Ccn1 in liver injury to understand its functions; (2) to determine whether CCN1 induces senescence in hepatic stellate cells; (3) to assess the role of CCN1 in regulating the Th1/Th2 balance in immune response; and (4) to test whether delivery or expression of CCN1 can prevent or ameliorate liver fibrosis. These studies will elucidate the roles of CCN1 as a critical regulator of the senescence program that copes with fibrosis, and may lead to the identification of new therapeutic targets and treatment strategies for reducing the morbidity and mortality associated with liver fibrosis. PUBLIC HEALTH RELEVANCE: Liver fibrosis is a result of sustained wound healing response to chronic liver injuries from such diverse causes as viral infections, alcohol abuse, and obesity, and can progress to cirrhosis in which serious and often live-threatening complications arise. This proposal seeks to understand the biologically programmed defense mechanisms that control liver fibrosis. We anticipate that results from these studies will prompt new therapeutic strategies that may reduce the morbidity and mortality associated with liver fibrosis.